Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of alpha-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the alpha-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson's disease has identified association of a SNP in SNCA with MSA

Agnes Camuzat

Alan Renton

Albert Ludolph

Alexandra Dürr

Alexis Brice

Ammar Al-Chalabi

Bernhard G. Landwehrmeyer

C Costa

G Bensimon

GD Mellick

Gilbert Bensimon

H Soma

HR Morris

I Yabe

J Infante

J Marchini

Jean-Sébastien Hulot

K Hara

Karen E. Morrison

M Nishimura

Michael H. Parkinson

Nicholas W. Wood

NJ Cairns

O Chiba-Falek

O Combarros

P Lewis

P Pals

P. Nigel Leigh

Prof. Peter Heutink

S Cho

S Gilman

S Purcell

Sigurd D. Sussmuth

SW Scholz

T Ozawa

U Wullner

V Plante-Bordeneuve

Y Furiya

Y Nakazato

Yves Agid

PubMed

BACKGROUND: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of alpha-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the alpha-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson's disease has identified association of a SNP in SNCA with MSA. METHODOLOGY/FINDINGS: We evaluated 32 SNPs in the SNCA gene in a European population of 239 cases and 617 controls recruited as part of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) study. We used 161 independently collected samples for replication. Two SNCA SNPs showed association with MSA: rs3822086 (P = 0.0044), and rs3775444 (P = 0.012), although only the first survived correction for multiple testing. In the MSA-C subgroup the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153, (95% CI 1.3-3.6); rs3775444 P = 0.0017, OR 4.386 (95% CI 1.6-11.7). A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7 x 10(-4)). The association with rs3822086 was replicated in the independent samples (P = 0.035). CONCLUSIONS/SIGNIFICANCE: We report a genetic association between MSA and alpha-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA. TRIAL REGISTRATION: ClinicalTrials.gov NCT00211224

Al-Chalabi, A

Durr, A

Wood, NW

Parkinson, MH

Camuzat, A

Hulot, JS

Morrison, Karen

Renton, A

Sussmuth, SD

Landwehrmeyer, BG

Ludolph, A

Agid, Y

Brice, Anne

Leigh, PN

Bensimon, G

University of Birmingham Research Portal

Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy

 with MSA. = 0.035).We report a genetic association between MSA and α-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA.

Al-Chalabi Ammar

Dürr Alexandra

Wood Nicholas W.

Parkinson Michael H.

Camuzat Agnes

Hulot Jean-Sébastien

Morrison Karen E.

Renton Alan

Sussmuth Sigurd D.

Landwehrmeyer Bernhard G.

Ludolph Albert

Agid Yves

Brice Alexis

Leigh P. Nigel

Bensimon Gilbert

Public Library of Science (PLOS)

 Are Associated with Multiple System Atrophy

Al-Chalabi, Ammar

Dürr, Alexandra

Wood, Nicholas W.

Parkinson, Michael H.

Camuzat, Agnes

Hulot, Jean-Sébastien

Renton, Alan

Sussmuth, Sigurd D.

Landwehrmeyer, Bernhard G.

Ludolph, Albert

Agid, Yves

Brice, Alexis

Leigh, P. Nigel

Bensimon, Gilbert

Queen's University Belfast Research Portal

Southampton (e-Prints Soton)

Background: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of alpha-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the alpha-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson's disease has identified association of a SNP in SNCA with MSA. Methodology/Findings: We evaluated 32 SNPs in the SNCA gene in a European population of 239 cases and 617 controls recruited as part of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) study. We used 161 independently collected samples for replication. Two SNCA SNPs showed association with MSA: rs3822086 (P = 0.0044), and rs3775444 (P = 0.012), although only the first survived correction for multiple testing. In the MSA-C subgroup the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153, (95% CI 1.3-3.6); rs3775444 P = 0.0017, OR 4.386 (95% CI 1.6-11.7). A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7 x 10(-4)). The association with rs3822086 was replicated in the independent samples (P = 0.035). Conclusions/Significance: We report a genetic association between MSA and alpha-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA

Duerr, Alexandra

Hulot, Jean-Sebastien

Morrison, Karen E.

King's Research Portal

Genetic Variants of the alpha-Synuclein Gene SNCA Are Associated with Multiple System Atrophy

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http://discovery.ucl.ac.uk/1348897/1/1348897.pdf

Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy.

Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy.

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University of Birmingham Research Portal

Public Library of Science (PLOS)

Queen's University Belfast Research Portal

Southampton (e-Prints Soton)

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